Orexin/hypocretin signaling at the orexin 1 receptor regulates cue‐elicited cocaine‐seeking

Abstract

The orexin/hypocretin system has recently been implicated in reward‐processing and addiction. We examined the involvement of the orexin system in cue‐induced reinstatement of extinguished cocaine‐seeking by administering the orexin 1 receptor antagonist SB‐334867 (SB) or the orexin 2 receptor antagonist 4‐pyridylmethyl (S)‐tert‐leucyl 6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline (4PT) prior to reinstatement testing. Male Sprague Dawley rats self‐administered cocaine in 2‐h sessions for 10 days, followed by extinction training. Reinstatement of cocaine‐seeking was elicited by presentation of tone + light cues previously paired with cocaine infusions. SB (10, 20 and 30 mg/kg) dose‐dependently decreased cue‐induced reinstatement of cocaine‐seeking without significantly affecting responding during late extinction. 4PT (10 and 30 mg/kg) did not significantly alter cue‐induced reinstatement. In separate experiments, the highest doses of SB and 4PT had no significant effect on established cocaine self‐administration, and 4PT reduced spontaneous activity in a locomotor test to a greater extent than SB. Finally, SB (30 mg/kg) had no effect on the acquisition of cocaine‐paired cues during a Pavlovian cocaine‐stimulus conditioning session in the operant chamber. Pretreatment with SB prior to the Pavlovian acquisition session had no effect on subsequent cue‐induced reinstatement of cocaine‐seeking elicited by those cues. However, pretreatment with SB prior to a second reinstatement session in the same animals significantly attenuated the expression of cue‐induced reinstatement. These results show that orexin transmission at the orexin 1 receptor, but not the orexin 2 receptor, is necessary for the reinstatement of cocaine‐seeking elicited by drug‐paired cues and that orexin signaling is not critical for cocaine reinforcement or cocaine‐stimulus conditioning.